Richard N. Kitsis, M.D.

Areas of Research: Fundamental mechanisms of cell death; molecular connections among death and autophagy programs; chemical biology; development of first small molecule drugs to reduce heart damage during myocardial infarction ("heart attack").

Professional Interests

CellDeath: Fundamental Mechanisms and Roles in Human Disease

The most basic decision that any cell makes is to grow, differentiate, or die. Our laboratory studies basic mechanisms of cell death, and the roles of cell death in normal biology and human disease.

Basic science

From a fundamental perspective, we are interested in how different death programs (in particular, apoptosis and necrosis) interconnect at the molecular level, and the mechanisms that determine whether a cell will die through one or another pathway. This is an important issue to understand because the modalities of cell death have dramatically different consequences with respect to collateral tissue damage. We have discovered some regulators that unite apoptosis and necrosis signaling, and therefore may serve as "decision points". One is the cell death inhibitor ARC that antagonizes multiple apoptosis and necrosis pathways through mechanisms that we have delineated (Molecular Cell, 2004; PNAS, 2007; JBC, 2007; Cell Death Differ, 2014; others). Another is the BCL-2 protein BAX. While BAX has been long recognized for its role in permeabilization of the outer mitochondrial membrane during apoptosis, we have discovered that it plays an unexpected critical role in regulating necrosis through distinct mechanisms (PNAS, 2012). These studies have serendipitously led us to recognize that BAX regulates not only cell death, but also influences multiple critical mitochondrial functions including dynamics and mitophagy. We hypothesize that these effects are mediated by different conformations of BAX, an area we are currently pursuing.

Translational research

While we have studied roles of cell death in cancer (Cell Death Differ, 2005; JBC, 2010; Cancer Res, 2011), diabetes (Diabetes, 2013), and pulmonary hypertension (Circulation, 2011), our most important translational accomplishments have focused on cell death in heart disease - specifically in the most common and lethal heart syndromes: myocardial infarction and heart failure. The lab was one of the founders of the cardiac cell death field and has played a major role in its development (Annu Rev Physiol, 2010) including the first demonstrations that regulated forms of cell death play central roles in the pathogenesis of myocardial infarction (J Mol Cell Cardiol, 2000; others) and heart failure (J Clin Invest, 2003; others). Currently, our translational work is focused on the chemical biology of cell death and, specifically, the development of small molecule drugs to reduce heart damage during myocardial infarction. While we have employed both unbiased screening of large chemical libraries (Probe Reports from the NIH Molecular Libraries Program, 2013), our current focus is on the development of the first BAX inhibitors, the rationale being that BAX is a critical mediator of both necrotic and apoptotic cell death during myocardial infarction. In addition to traditional biochemical/molecular/cellular approaches, the latter work involves chemistry and structural biology (the latter in collaboration with Dr. Evripidis Gavathiotis) and small and large animal models.

I supervise a laboratory of approximately 10, including Ph.D. and M.D./Ph.D. students and postdocs. An important facet of my work is training and mentorship. I have been thesis research advisor to 11 individuals who have received the Ph.D. degree. A significant proportion of my trainees have gone on to academic faculty positions as independent investigators. My pre- and postdoctoral trainees have included a substantial number of individuals from groups under-represented in science.